PROJECT SUMMARY Idiopathic pulmonary fibrosis (IPF) is a devastating disorder of unknown etiology with a median survival of only 2-3 years. The rate of disease progression for individuals with IPF is highly variable. Rapid progression occurs in only 20-30% of patients but is responsible for 75% of IPF-related deaths. A major problem facing clinicians is that they are unable to identify patients that will experience rapid progression until after irreversible lung function decline occurs. Dr. Newton has previously demonstrated that pathogenic genetic variants in telomere- maintenance genes predispose to rapid progression; however, these static genetic variants alone do not explain the extreme heterogeneity in IPF clinical course. The variability in clinical course is strongly influenced by environmental exposures such as cigarette smoke or inflammation, which can alter chromatin structure and availability of gene regulatory elements, thus reprogramming gene expression profiles that produce divergent IPF disease course phenotypes. Therefore, Dr. Newton hypothesizes that integrating chromatin accessibility with gene expression will allow for the discovery of novel molecular markers and biologically relevant driver pathways that differentiate IPF disease course phenotypes. Along these lines, his Specific Aims are to 1) identify IPF patients at high-risk for short-term rapid progression using clinical, genomic, epigenetic, and gene expression signatures, 2) discover gene regulatory elements and biologic pathways that are associated with rapid IPF progression, and 3) identify changes in chromatin accessibility and gene expression that correspond to acute IPF exacerbations. To accomplish these aims, he has established a prospective IPF cohort designed to perform serial blood collection while simultaneously quantifying the rate of IPF progression. Using RNA and DNA from blood lymphocytes of IPF patients collected longitudinally as their disease evolves, he will integrate transcriptome patterns with chromatin features to identify biologic pathways in easily accessible blood cells that signify high-risk IPF. The data generated from these aims will form the foundation for two subsequent independent proposals that will seek to validate a blood-based molecular profile that identifies IPF patients at high-risk for rapid progression, and explore and biologically validate the influence epigenetic regulation on gene expression patterns and driver pathways within the context of IPF disease course. Dr. Newton has a sustained track record of high-impact translational research using genetic and genomic markers to predict clinical outcomes in pulmonary fibrosis. This K23 will allow him to obtain the necessary training to expand his technical skills and expertise in developing and validating novel biomarkers, constructing clinically useful prediction models, and integrating next-generation sequencing technologies. His mentoring team is composed of highly accomplished scientific mentors with expertise in genetics, epigenetics, molecular biology, bioinformatics, statistics, and IPF disease behavior. This K23 is geared toward his goal of becoming an independent physician-scientist whose research improves the clinical care of IPF patients.